Abstract 3688: Interferon-gamma, a Th1 Cytokine, Regulates Fat Inflammation: A Role for Adaptive Immunity in Obesity
Background. Adipose tissue (AT) accumulates macrophages and can produce various cytokines in obesity. While innate immune responses play a well-recognized part in the obesity inflammatory network, the role of adaptive immunity in AT remains poorly explored.
Methods and Results. Visceral AT of diet-induced obese C57BL/6 mice contained higher numbers of both CD4+ and CD8+ T lymphocytes than lean controls (respectively, 2150±57 vs 1610±95 and 780±110 vs 346±58 cells/2.5x104 stromal vascular cells p<0.05), analyzed by FACS. T cells from obese visceral AT produced more interferon-gamma (IFNγ) after polyclonal activation in vitro than did those from lean AT. In addition to higher expression of macrophage and T cell markers (CD45, Mac-3 and CD3), AT from obese animals also had more cells expressing I-Ab, a mouse class II histocompatibility marker suggestive of T cell activation, as determined by IHC. Differentiated murine 3T3-L1 cells stimulated with T helper-1 (Th1)-derived supernatant produced more IFNγ-inducible protein (IP-10), a process reversed by IFNγ blocking antibodies. Microarray analysis of IFNγ-treated 3T3-L1 cells showed greater expression of several CC- and CXC-chemokines than untreated cells (n=6). Compared to wild type mice with diet-induced obesity, obese IFNγ−/− animals had significantly reduced AT expression of mRNA encoding inflammatory genes such as tumor necrosis factor alpha (TNFα) (0.34-fold p=0.05), monocyte chemoattractant protein-1 (MCP-1) (0.38-fold p<0.02), and regulated on activation, normal T cell expressed and secreted (RANTES) (0.32-fold p<0.05); fewer inflammatory cells by IHC (210.2±62 vs 148.2±29 cells/10 fields p=0.05); and a trend toward better glucose tolerance (n=5– 6). Obese mice doubly deficient for IFNγ receptor and ApoE had decreased AT expression of important T cell-related genes, such as IP-10 (0.39-fold p=0.02), monokine induced by IFNγ (MIG) (0.37-fold p<0.05), RANTES (0.17-fold p<0.001), and I-Ab (0.583-fold p=0.05; n=5 for all genes), and lower plasma triglycerides and glucose (n=9).
Conclusions. These results indicate a role for T cells and IFNγ, a prototypical Th1 cytokine, in driving the inflammatory network operating during obesity.